Project 3 has developed new approaches for targeting brain tumors using lipidic nanoparticle-based drugs, ncluding novel liposomes and immunoliposomes. These advances include: new and extremely robust technologies for drug loading and stabilization, resulting in novel nanoliposomal drugs that can deliver a number of anticancer compounds to brain tumors; antibody-targeted constructs (immunoliposomes) against EGFR and/or EGFRvlll; the first successful demonstration of convection-enhanced delivery (CED) of lipidic nanoparticles in the CMS; and imaging of drug delivery using CED of liposomal gadolinium (Gd). One of these novel agents, nanoliposomal CPT-11, has shown highly promising preclinical efficacy and has entered clinical trials as a systemic treatment. Using a clinically validated liposome-based scaffold, we can engineer additional capabilities to generate innovative and multifunctional nanoparticles for targeted delivery of anticancer drugs, either by systemic or CED routes. We now hypothesize that CED of lipidic nanoparticle- based agents combining drug delivery with imaging capability can provide targeted therapy of brain tumors. Our ongoing studies infusing lipidic nanoparticles into the brain via CED have exceeded our expectations as a robust and clinically applicable approach for the treatment of brain tumors, including the potential for targeting via MRI guidance. Accordingly, we will develop multifunctional nanoparticle-based systems for integrated image-guided therapy, combining encapsulated drugs and MRI probes and optimized for CED infusion to brain tumors. Our Aims include: 1) Develop lipidic nanoparticle/CED imaging strategy via co- infusion system or multifunctional nanoparticles co-encapsulating Gd + drug; 2) Evaluate other lipidic nanoparticle agents in conjunction with image-guided CED, including other cytotoxic drugs and siRNA; 3) Evaluate immunoliposome targeting combined with CED; and 4) Translate best multifunctional lipidic nanoparticle agent/strategy to clinical trial. Lay summary: We are studying new approaches to deliver drugs more efficiently to brain tumors using nanoparticle agents (sub-microscopic carriers of drugs). We propose to infuse these particles directly into the brain to target brain tumors, and will use MRI to guide this treatment.